The Journal of Clinical Pharmacology最新文献

{"title":"In Vivo Activity of Intestinal P-Glycoprotein and Hepatic Organic Anion Transporters Polypeptide in Pregnancy and Postpartum","authors":"Álef Machado Gomes Pego MA,&nbsp;Maria Paula Marques PhD,&nbsp;Fernanda de Lima Moreira PhD,&nbsp;Tiago Paz PhD,&nbsp;Maria Martha de Barros Tarozzo MA,&nbsp;Rogério Pereira Mattos MA,&nbsp;Patrícia Pereira dos Santos Melli PhD, MD,&nbsp;Geraldo Duarte PhD, MD,&nbsp;Ricardo Carvalho Cavalli PhD, MD,&nbsp;Vera Lucia Lanchote PhD","doi":"10.1002/jcph.6125","DOIUrl":"10.1002/jcph.6125","url":null,"abstract":"<p>This study investigates the influence of pregnancy on the <i>in vivo</i> activity of the intestinal P-glycoprotein (P-gp) and hepatic organic anion transporters polypeptide (OATP/BCRP) using, respectively, fexofenadine and rosuvastatin as probe drugs. Eleven healthy participants were investigated during the third trimester of pregnancy (Phase 1, 28 to 38 weeks of gestation) and in the postpartum period (Phase 2, 8 to 12 weeks postpartum). In both phases, after administration of a single oral dose of fexofenadine (60 mg) and rosuvastatin (5 mg), serial blood samples were collected for up to 24 h. Rosuvastatin and fexofenadine in plasma were analyzed by LC-MS/MS using previously validated methods. The pharmacokinetic parameters of fexofenadine and rosuvastatin (Phoenix WinNonLin software) with normal distribution (Shapiro–Wilk test) are presented as geometric mean and 90% confidence interval. Phases 1 and 2 were compared using the t test (<i>P</i> &lt; .05). Fexofexadine AUC_0-24 values do not differ (<i>P-</i>value: .0715) between Phase 1 (641.9 ng h/mL [500.6-823.1]) and Phase 2 (823.8 ng h/mL [641.5-1057.6]) showing that pregnancy (third trimester) does not alter intestinal P-gp activity. However, rosuvastatin AUC_0-24 values are higher (<i>P-</i>value: .00005) in Phase 1 (18.7 ng h/mL [13.3-26.4]) when compared to Phase 2 (9.5 ng h/mL [6.7-13.4]), suggesting inhibition of OATP1B1/OATP1B3 transporters. In conclusion, pregnancy assessed during the third trimester does not alter the intestinal P-gp activity but reduces the activity of hepatic OATP1B1/OATP1B3 transporters. Therefore, adjustments in dosage regimens may be necessary for drugs with low therapeutic index, substrates of the OATP1B1/OATP1B3 transporters, administered during the third trimester of pregnancy.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 1","pages":"7-17"},"PeriodicalIF":0.0,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142074280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of Obesity-Related Physiological Changes on Pantoprazole Clearance in Children Using a Population Pharmacokinetic Approach","authors":"Tyler C. Dunlap PharmD,&nbsp;Daniel Gonzalez PharmD, PhD,&nbsp;Kathryn E. Kyler MD, MS,&nbsp;Victória Etges Helfer PhD,&nbsp;Veronica Williams RN, CCRC,&nbsp;Chance S. Friesen BS,&nbsp;Nathan Artz PhD,&nbsp;Sherwin Chan MD, PhD,&nbsp;Valentina Shakhnovich MD","doi":"10.1002/jcph.6122","DOIUrl":"10.1002/jcph.6122","url":null,"abstract":"<p>Pediatric obesity is a growing health concern, affecting millions of children worldwide. While pharmacokinetic (PK) changes in numerous commonly prescribed medications have been linked to obesity, the physiological mechanisms driving these alterations and their implications for drug dosing remain poorly understood. The objective of this study was to evaluate previously reported observations of reduced pantoprazole clearance (CL) in children with obesity, investigate obesity-related characteristics in liver physiology as explanatory causes for these observations, and evaluate the clinical relevance of obesity on drug dosing. A prospective, comparative PK study, enrolling participants 6-21 years of age, with and without obesity, was conducted to evaluate the association between obesity-related characteristics and pantoprazole CL. A nonlinear mixed-effects modeling approach was used to identify sources of interindividual variability in pantoprazole PK. Monte Carlo simulations were performed to assess pantoprazole exposure in children and evaluate the association between obesity and pantoprazole exposure. The study population consisted of 39 pediatric participants: 31% without obesity and 69% with obesity. A two-compartment PK model with covariate effects of total body weight (TBW), CYP2C19 metabolizer phenotype, and obesity status adequately described the PK data. After accounting for differences due to TBW and CYP2C19 metabolizer phenotype, obesity was associated with an estimated 18% reduction in pantoprazole CL (comparable to the reduction estimated for a <i>CYP2C19</i> loss of function allele). Further research is warranted to evaluate the physiological mechanisms associated with reduced drug CL in children with increased body size and the implications for drug dosing.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 1","pages":"108-120"},"PeriodicalIF":0.0,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142074279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reply to: Comment: Cerebrospinal Fluid Pharmacokinetics of Nicardipine Following Intrathecal Administration in Subarachnoid Hemorrhage Patients","authors":"Ofer Sadan MD, PhD,&nbsp;Yoo-Seong Jeong PhD,&nbsp;Shany Cohen-Sadan MD,&nbsp;Eashani Sathialingam PhD,&nbsp;Erin M. Buckley PhD,&nbsp;Prem A. Kandiah MD,&nbsp;Jonathan A. Grossberg MD,&nbsp;William Asbury PharmD,&nbsp;William J. Jusko PhD,&nbsp;Owen B. Samuels MD","doi":"10.1002/jcph.6123","DOIUrl":"10.1002/jcph.6123","url":null,"abstract":"&lt;p&gt;To the editor,&lt;/p&gt;&lt;p&gt;We appreciate the interest of Drs. Du and Chen in our recent manuscript describing a pharmacokinetic model for intermittent intrathecal nicardipine administration.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; The authors mentioned a few details that were omitted from our manuscript. These omissions were primarily due to prioritizing critical details in a limited space. We are happy to use the current space to further shed light on our clinical investigation.&lt;/p&gt;&lt;p&gt;First, with regard to sample storage, the hourly cerebrospinal fluid (CSF) (or plasma) samples were collected and initially stored on ice while protected from light. After completing the of sample collection for each dose tested, the entire set of samples was aliquoted and kept in a −80°C freezer. All the samples from all subjects in this cohort were measured as a single batch.&lt;/p&gt;&lt;p&gt;Second, the Du and Chen mention that we did not report certain patient outcomes. However, we clearly stated that the purpose of our study was to determine the pharmacokinetics of nicardipine in the CSF of a limited number of patients with subarachnoid hemorrhage. Many of the clinical aspects of intrathecal (IT) nicardipine administration were reported previously in a larger, better powered cohort.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Reporting patient outcomes in an underpowered small cohort may lead to the misinterpretation of efficacy. Therefore, despite the encouraging clinical outcomes observed in the current cohort, we chose not to publish them herein. As noted in our manuscript, we agree that larger and more rigorously designed studies are needed in the future to develop an optimal dosing strategy for IT nicardipine based on integrative pharmacokinetic/pharmacodynamic (PK/PD) assessment of patient outcome data.&lt;/p&gt;&lt;p&gt;Third, Du and Chen mentioned a single center small cohort study that reported an alternative IT nicardipine administration approach using a cisternal drain.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Per this report, cisternal drain placement occurred during microsurgical clipping rather than during endovascular repair of the aneurysm as Du and Chen mistakenly stated. Since the endovascular approach is associated with improved patient outcomes (see International Subarachnoid Aneurysmal Trial [ISAT] &lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;), it is unclear to us how mentioning the work of Vandenbulcke et al. in relationship to ours is relevant.&lt;/p&gt;&lt;p&gt;Furthermore, Du and Chen incorrectly claimed that q12hr dosing is the most common frequency for intrathecal nicardipine. This might be true at their center. Indeed, in a new clinical trial originated from The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China (FAST-IT trial, NCT06329635) this was the regimen chosen. However, prior to our report, a dose range of 2–10 mg q8hr or q6hr dosing was reported in 6 different papers involving 548 patients,&lt;span&gt;&lt;sup&gt;2, 5-9&lt;/sup&gt;&lt;/span&gt; while a dosing regimen of 4 mg q12hr was reported in 4 papers involving 192 patients.&lt;","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 1","pages":"145-146"},"PeriodicalIF":0.0,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.6123","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142074281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prostatic Pharmacokinetic and Pharmacodynamic Analysis of Ceftazidime: Dosing Strategy for Bacterial Prostatitis","authors":"Tetsushu Onita PhD,&nbsp;Kogenta Nakamura MD,&nbsp;Genya Nishikawa MD,&nbsp;Noriyuki Ishihara PhD,&nbsp;Hiroki Tamaki PhD,&nbsp;Takahisa Yano PhD,&nbsp;Kohji Naora PhD,&nbsp;Norifumi Morikawa PhD,&nbsp;Kazuro Ikawa PhD","doi":"10.1002/jcph.6119","DOIUrl":"10.1002/jcph.6119","url":null,"abstract":"<p>This study aimed to develop a prostatic pharmacokinetic model of ceftazidime and suggest more effective dosing strategy for the bacterial prostatitis, based on a site-specific pharmacokinetic and pharmacodynamic perspective. Subjects were prostatic hyperplasia patients prophylactically receiving a 0.5-h infusion of 1.0 g or 2.0 g ceftazidime before transurethral resection of the prostate. Plasma and prostate samples were premeditatedly collected after the administration and the concentrations were measured by high-performance liquid chromatography. The prostate tissue/plasma ratio in area under the drug concentration-time curve was approximately 0.476. The prostatic population pharmacokinetic model incorporated creatinine clearance (CL_cr) into ceftazidime clearance was developed, and adequately predicted prostate tissue concentrations by diagnostic scatter plots and visual predictive checks. Aiming for a bactericidal target of 70% of time above minimum inhibitory concentration (T &gt; MIC) in prostate tissue, 2.0 g twice daily achieved ≥90% expected probability against main pathogens like <i>Escherichia coli</i> and <i>Proteus</i> species in patients regardless of renal function (CL_cr = 60 and 90 mL/min). However, since the expected probability of attaining the bactericidal target of 0.5-h infusion dosing regimen did not achieve 90% against <i>Pseudomonas aeruginosa</i> in patients with CL_cr = 60 and 90 mL/min, 4-h infusion dosing regimen of 2.0 g three times daily (6 g/day) might be required for empirical treatment. Based on site-specific simulations, the present study provides more effective dosing strategy for bacterial prostatitis.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 1","pages":"121-131"},"PeriodicalIF":0.0,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142057038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comment: Cerebrospinal Fluid Pharmacokinetics of Nicardipine Following Intrathecal Administration in Subarachnoid Hemorrhage Patients","authors":"Xiaolin Du MD,&nbsp;Guangtang Chen MD","doi":"10.1002/jcph.6124","DOIUrl":"10.1002/jcph.6124","url":null,"abstract":"&lt;p&gt;To the Editor,&lt;/p&gt;&lt;p&gt;We recently read with great interest the article by Sadan et al.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; This study, using data from 16 subarachnoid hemorrhage (SAH) patients, successfully developed a population pharmacokinetic (popPK) model to describe the nicardipine disposition kinetics in the cerebrospinal fluid (CSF) following intrathecal (IT) administration. However, we noted that the authors may have overlooked several important factors during the execution of the study. We want to offer the following suggestions for the author's consideration.&lt;/p&gt;&lt;p&gt;First, there are issues concerning the details of sample collection, storage, and analysis. We observed discrepancies in the reported times of CSF and blood collection. Additionally, the storage conditions and analysis timing of the samples were not specified. Considering that CSF was collected hourly, up to 6 or 8 h, the authors should clarify whether the samples were stored at −80°C and analyzed collectively once all samples were collected. These details are crucial as they may affect the concentration measurements of nicardipine and the comparability of samples, which could impact the reliability of the experimental model.&lt;/p&gt;&lt;p&gt;Second, the study indicates that IT nicardipine may cause side effects such as hydrocephalus, leading to an increased need for CSF shunting procedures.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; However, the study did not mention the occurrence of hydrocephalus in these 16 patients in either the short or the long term. This omission limits the ability to analyze the correlation between CSF nicardipine concentrations and the incidence of hydrocephalus. Furthermore, as noted by the authors, there is not enough high-level evidence to support the improvement of SAH patient outcomes with IT nicardipine.&lt;span&gt;&lt;sup&gt;3, 4&lt;/sup&gt;&lt;/span&gt; However, the study lacks specific clinical outcome data for these 16 patients (e.g., neurological recovery and survival rates), which restricts the clinical relevance and applicability of the findings. These factors should be considered in future research designs.&lt;/p&gt;&lt;p&gt;Third, research suggests that cisternal nicardipine (CN) is more effective than the external ventricular drain (EVD) route, but the mechanism remains unclear.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; CN is typically used in patients treated by coiling, while EVD is used for those treated by microsurgical clipping. We propose that the superior efficacy of nicardipine in patients treated with coiling compared to those undergoing microsurgical clipping may be due to the fact that the blood–brain barrier in the former is not disrupted, thereby preventing systemic hypotension from CSF nicardipine leakage. Future studies incorporating a CN group based on the study protocol of Sadan et al. could help validate this mechanism. Additionally, since every 12-h administration of 4 mg nicardipine is the most common dosing regimen, future research might consider this dosing scheme to avoid frequent IT administratio","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 1","pages":"143-144"},"PeriodicalIF":0.0,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.6124","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142047364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Simultaneously Predicting Pharmacokinetics of Loratadine and Desloratadine in Children Using a Whole-Body Physiologically Based Pharmacokinetic Model","authors":"Tianlei Liu MD,&nbsp;Ruijing Mu PhD,&nbsp;Xiaodong Liu PhD","doi":"10.1002/jcph.6120","DOIUrl":"10.1002/jcph.6120","url":null,"abstract":"<p>Loratadine is metabolized to desloratadine. Both of them have been used for allergy treatment in children. Anatomical, physiological, and biological parameters of children and clearance of drugs vary with age. We aimed to develop a whole-body physiologically based pharmacokinetic (PBPK) model to simultaneously predict the pharmacokinetics of loratadine and desloratadine in children. Following validation using 11 adult data sets, the developed PBPK model was extrapolated to children. Plasma concentrations following oral loratadine or desloratadine to children of different ages were simulated and compared with six children data sets. After scaling anatomy/physiology, protein binding, and clearance, pharmacokinetics of the two drugs in pediatric populations were satisfactorily predicted. Most of the observed concentrations fell within the 5th-95th percentile range of the simulations in 1000 virtual children. The predicted area under the concentration-time curve (AUC) and C_max fell within 0.5-2.0-fold range of the observations. Oral doses of loratadine or desloratadine for children of different ages were simulated based on similar AUCs following 10 mg of loratadine or 5 mg of desloratadine for adults. Pediatric PBPK model was successfully developed to simultaneously predict plasma concentrations of loratadine and desloratadine in children of all ages. The developed pediatric PBPK model may also be applied to optimize pediatric dosage.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 1","pages":"74-86"},"PeriodicalIF":0.0,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142019284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First-in-Human Study of the Safety, Tolerability, Pharmacokinetics, Immunogenicity, and Pharmacodynamics of DS-7011a, an Anti-TLR7 Antagonistic Monoclonal Antibody for the Treatment of Systemic Lupus Erythematosus","authors":"Giorgio Senaldi MD, PhD,&nbsp;Aparna Mohan MD, PhD,&nbsp;Li Zhang MD, PhD, FCP,&nbsp;Jun Tanaka PhD,&nbsp;Yong Lin PhD,&nbsp;Grishma Pandya BS,&nbsp;Sindee Grossman BA,&nbsp;Sarah Urbina MS,&nbsp;Steven H. Reynolds DO,&nbsp;Alan H. Hand MD","doi":"10.1002/jcph.6117","DOIUrl":"10.1002/jcph.6117","url":null,"abstract":"<p>Toll-like receptor (TLR)7 is a pattern recognition receptor that critically contributes to the pathogenesis of systemic lupus erythematosus (SLE). DS-7011a is an anti-TLR7 monoclonal antibody that prevents TLR7 from signaling. The aim of this first-in-human, double-blind, randomized, and placebo-controlled study was to evaluate the safety, pharmacokinetics, immunogenicity, and pharmacodynamics of single ascending intravenous (IV) and subcutaneous (SC) doses of DS-7011a in healthy subjects (HS) (NCT05203692). On day 1, 80 HS received DS-7011a or placebo 6:2 in 10 cohorts (7 treated IV and 3 SC) of 8 each and were followed for 8 weeks until day 57. Safety was evaluated by recording treatment-emergent adverse events (TEAEs), pharmacokinetics by measuring plasma DS-7011a, immunogenicity by measuring plasma anti-drug antibodies (ADAs), and pharmacodynamics by evaluating the suppression of interleukin-6 production ex vivo in whole blood. DS-7011a was safe and well tolerated across all cohorts. TEAEs were mostly mild in severity and not drug-related. DS-7011a exposure increased with the dose but was not dose proportional, as the elimination of lower doses was accelerated by target-mediated drug disposition. Terminal half-life was about 15-17 days and T_max upon SC administration was about 5 days. DS-7011a induced ADAs in about half of HS but with no impact on clinical findings and pharmacokinetics. Pharmacodynamic (PD) response also increased with the dose and at the higher doses was of large extent (&gt;90%), early onset, and lasting duration. DS-7011a showed favorable safety, pharmacokinetics, immunogenicity, and PD properties that support its development for the treatment of SLE.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 1","pages":"41-52"},"PeriodicalIF":0.0,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142019283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Randomized, Parallel, Open-Label, Single-Dose and Multiple-Dose Clinical Trial to Investigate the Pharmacokinetic, Pharmacodynamic, and Safety Profiles of Obicetrapib in Healthy Participants in China","authors":"Jing Zhang MD, PhD,&nbsp;Guoying Cao MD,&nbsp;Yong Huo MD,&nbsp;Liana L. Guarneiri PhD, RDN,&nbsp;Marc Ditmarsch MD,&nbsp;John J. P. Kastelein MD, PhD,&nbsp;Douglas Kling MBA,&nbsp;Andrew Hsieh PharmD,&nbsp;Erin Wuerdeman MS,&nbsp;Michael H. Davidson MD","doi":"10.1002/jcph.6121","DOIUrl":"10.1002/jcph.6121","url":null,"abstract":"<p>Obicetrapib is a selective cholesteryl ester transfer protein (CETP) inhibitor. Previous research has demonstrated similar pharmacokinetic (PK) responses to single doses of obicetrapib between Japanese and White males, but the PK responses have not been established in Chinese individuals. The purpose of this randomized, parallel, open-label trial was to characterize the PK and pharmacodynamic (PD; CETP activity and plasma lipids) responses and safety of single doses (5, 10, or 25 mg; N = 36) and multiple doses (10 mg for 14 days; N = 12) of obicetrapib in healthy Chinese individuals. The maximum concentration and area under the drug concentration-time curve of obicetrapib from 0 h to infinity increased with dose after all single doses of obicetrapib. After 7 consecutive days of dosing, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol reached their minimum and maximum changes of 42% reduction and 108% increase, respectively. Primary PK and PD parameters after single- and multiple-dose administration of obicetrapib were similar to those in healthy white participants in previous studies. One participant in the 5 mg dose group experienced a treatment-emergent adverse event of decreased white blood cell and neutrophil counts, which resolved without intervention. In conclusion, these findings support the inclusion of Chinese individuals in the ongoing phase 3 clinical development program of obicetrapib.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 1","pages":"96-107"},"PeriodicalIF":0.0,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11683177/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142001112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetics (PopPK) Support for Pediatric Dosing of Biological Products","authors":"Brianna Eales PhD,&nbsp;Nada A. Helal PhD,&nbsp;Olivia Vattelana BS,&nbsp;Mohamad M. Kronfol PhD,&nbsp;Elimika Pfuma Fletcher PhD,&nbsp;Yow-Ming Wang PhD,&nbsp;Gilbert J. Burckart PharmD,&nbsp;Jayabharathi Vaidyanathan PhD,&nbsp;Shirley K. Seo PhD,&nbsp;Mohamed Ismail Nounou PhD","doi":"10.1002/jcph.6116","DOIUrl":"10.1002/jcph.6116","url":null,"abstract":"<p>This study assesses the use of population pharmacokinetics (PopPK) in supporting pediatric dosing of novel biological drug products. The labeling for biologic drug products approved by the US Food and Drug Administration (FDA) from 2002 until 2021 was reviewed to identify those with a pediatric indication. For the drugs with a pediatric indication, the dosing regimen(s) based on age groups, dosing strategy, the use of PopPK to support the dose, and the types of pediatric clinical trials were reviewed. Data were collected from FDA's review documents and product labels on the Drugs@FDA website, and as needed, more clinical trial details were collected from PubMed and clinicaltrials.gov. The role of PopPK analyses in dosing was captured when mentioned in the label or review as playing a role in selecting the approved pediatric dose and/or in verifying the adequacy of the studied dose to support labeling. Between 2002 and 2021, FDA approved 169 biological products, and 78 of 169 (46%) products have an approved indication for which the label contains dosing recommendations for pediatric use. For the 78 products approved in pediatrics, there was a total of 180 clinical trials that included pediatric patients. Phase 3 pediatric trials commonly supported pediatric approval and dosing for the reviewed products (64%, 50/78 products; 56.1%, 101/180 trials). PopPK analyses were reported to play a critical role in dose selection, prediction, and verification for 40 of the 78 products (51%), including informing pediatric dosing in the absence of pediatric data (e.g., drugs approved under animal rule), comparing exposures to the exposure range observed in adults, and informing alternative dosing strategies in certain age or body weight groups. PopPK analyses have been applied in a variety of ways to inform pediatric dosing and support extrapolation from adult data or other pediatric age groups for biologics. Understanding and learning from these past cases on the use of pharmacometrics tools to support pediatric dosing of biological products can inform future pediatric development programs.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"64 12","pages":"1594-1605"},"PeriodicalIF":0.0,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141989282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tracing the Evolution: A Comprehensive Bibliometric Analysis of Drug Interaction Clinical Studies","authors":"Lanping Li MSc,&nbsp;Yushi Zhou MSc,&nbsp;Lika Ye MSc,&nbsp;Zhihong Xie MSc","doi":"10.1002/jcph.6112","DOIUrl":"10.1002/jcph.6112","url":null,"abstract":"<p>This study aims to meticulously map the bibliometric landscape of drug-drug interactions (DDIs) in clinical research. This represents the first use of bibliometric analysis to comprehensively highlight the evolutionary trends and core themes in this critical field of pharmacology. An exhaustive bibliometric search was performed within the Web of Science Core Collection, aiming to comprehensively gather literature on DDIs in clinical settings. A combination of sophisticated analytical tools including DIKW, VOSviewer, and Citespace was utilized for an in-depth exploration of bibliometric patterns and trends. Of the 3421 initially identified articles, 2622 were considered relevant. The analysis revealed a marked escalation in DDIs publications, with a peak observed in 2020. Five principal thematic clusters emerged: Safety and Adverse Reactions, Drug Metabolism and Efficacy, Disease and Drug Treatment, Research Methods and Practices, and Special Populations and Combined Medication. Key insights included the escalating significance of drug metabolism in pharmacokinetics, heightened focus on cardiovascular and antiviral therapeutics, and the advancing frontier of personalized medicine. Additionally, the analysis underscored the necessity for strategic attention to vulnerable populations and innovative methodological approaches. This study calls for the global harmonization of research methods in DDIs clinical investigations, advocating for the integration of personalized medicine paradigms and the implementation of cutting-edge computational analytics. It highlights the imperative for inclusive and collaborative research approaches to adeptly address the intricate challenges of contemporary pharmacotherapy.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"64 12","pages":"1505-1516"},"PeriodicalIF":0.0,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}